1. Field of the Invention
This invention relates to novel indanyloxyacetic acid derivatives more specifically described as 1-oxo-2-(optionally substituted)phenyl-2-alkynyl-5-indanyloxyacetic acids. These compounds have drug and bio-affecting properties and, in particular, are diuretic and uricosuric agents with relatively low toxicity. The invention is also concerned with a method for preparing the indanyloxyacetic acid compounds and novel silylated intermediates therefor.
2. Description of the Prior Art
Cragoe, Jr., et al., U.S. Pat. No. 4,096,267 concerns (1-oxo-2-aryl-2-substituted-5-indanyloxy)alkanoic acids having diuretic, saluretic, and uricosuric activity. The following specific compounds of Formula (1) illustrate alkyl- and alkenyl-2-substituents.
______________________________________ ##STR1## Formula (1) R ______________________________________ (1a) methyl (1b) allyl ______________________________________ *Ph = phenyl
According to the U.S. Pat. No. 4,096,267, such compounds are prepared by various processes including an etherification step illustrated by the flow diagram below of the procedure of Example 1 (Step E). ##STR2## (1-Oxo-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid (3) is obtained according to the above flow diagram in a relatively low yield of about 6% with recovery of starting material even though an extended reaction period of some 48 hours was employed.
deSolms, et al., J. Med. Chem., 21, 437-443 (1978) discusses structure-activity relationships of the (2-alkyl-2-aryl-1-oxo-5-indanyloxy)acetic acids of U.S. Pat. No. 4,096,267. The article identifies the preferred compound of the series as (6,7-dichloro-2-methyl-1-oxo-2-phenyl-5-indanyloxy)acetic acid (MK-196). Using this compound as a standard for comparison, the authors concluded that as the "2-alkyl substituent" increases in size from methyl to ethyl, etc., activity drops considerably.
Cragoe, Jr., et al., U.S. Pat. No. 3,984,465 is concerned with (1-oxo-2-alkyl-2-substituted-5-indanyloxy)acetic acids having diuretic, saluretic, and uricosuric activity. Generically disclosed indanyloxyacetic acids include compounds wherein 2-substituents are alkyl, alkenyl, or alkynyl. The following compounds of formula (4) illustrating alkyl- and alkenyl-2-substituents are specifically disclosed in the U.S. Pat. No. 3,984,465. However, the patent does not describe or set forth in any manner a specific example of a "2-alkynyl" substituted indanyloxyacetic acid.
______________________________________ ##STR3## Formula (4) R ______________________________________ (4a) methyl (4b) ethyl (4c) allyl ______________________________________
Cragoe, Jr., U.S. Pat. No. 4,070,539 concerns 2-alkyl derivatives of 1-oxo-5-indanyloxyalkanoic acid which are said to be diuretic and saluretic. Some of the compounds are reportedly also capable of maintaining or reducing uric acid levels.
Waltersdorf, Jr. et al., J. Med. Chem. 20, 1400-1408 (1977) discusses diuretic structure-activity relationships of certain (1-oxo-5-indanyloxy)acetic acids having a mono-alkyl substituent in the 2-position or bearing an additional "2-substituent" such as alkyl or allyl. The compounds studied were prepared according to processes described in Cragoe, et al., U.S. Pat. Nos. 3,984,465 and 4,070,539.
The instant invention provides a process for preparing indanyloxy compounds of Formula I (infra) involving selective etherification of a 2-(phenyl)-substituted-5-hydroxyindanone with ethyl bromoacetate to the corresponding indanyloxyacetate and subsequent alkynylation of the "2-position" with a "protected" alkynyl halide such as trimethylsilylpropargyl bromide followed by hydrolysis of the alkynyl intermediates. This process constitutes a decided improvement over analogous prior art procedures of Cragoe, et al., U.S. Pat. Nos. 4,070,539 and 4,096,267, in that substantially improved yields are obtained.